Determining the role of flavin-containing monooxygenase-2 in longevity regulation

确定含黄素单加氧酶 2 在长寿调节中的作用

基本信息

批准号：
10393591
负责人：
Christopher Ian Choi
金额：
$ 0.66万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-16 至 2022-06-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10393591
关键词：
Aging Alzheimer&apos s Disease Animal Model Bacteria Biochemical Pathway Biochemistry Biological Assay Biology of Aging Caenorhabditis elegans Carbon Cardiovascular Diseases Catalytic Domain Cause of Death Computer Models Data Data Analyses Disease Economics Energy Metabolism Ensure Enzymes FMO2 FMO3 Family Family member Fishes Folic Acid Gene Expression Gene Proteins Genes Genetic Goals Health Health Benefit Heart Diseases Human Hypoxia In Vitro Isotope Labeling Isotopes Knock-out Knowledge Life Extension Longevity Longevity Pathway Measures Mediating Metabolic Metabolic Pathway Metabolism Methylation Methyltransferase Modeling Molecular Mus Mutation Nematoda Nitrogen Odors Output Pathway interactions Persons Play Process Protein Family Proteins RNA Interference Reaction Regulation Reporting Research Risk Factors Role Signal Transduction Sulfur Sulfur Amino Acids Syndrome System Systems Analysis Testing Tracer Xenobiotics aging population amino acid metabolism base cancer type dietary dietary restriction experimental study flavin-containing monooxygenase follow-up glucose metabolism human old age (65+)improved in silico in vitro activity knock-down lipid metabolism member metabolomics mouse model nucleotide metabolism overexpression predictive modeling prevent response small molecule success therapeutic target transcriptomics transmethylation trimethylamine trimethyloxamine

项目摘要

Project summary. Aging is the greatest risk factor for multiple leading causes of death, such as heart diseases, multiple types of cancer, and Alzheimer’s disease. Aging is thus a growing economic and health concern worldwide as the number of people over the age of 65 continues to increase. Multiple genetic and environmental pathways that slow aging, such as dietary restriction (DR) and hypoxic response, have been discovered using animal models. However, the mechanisms by which these pathways extend lifespan remain largely unclear. This project focuses on a member of the family of xenobiotic metabolizing enzymes, flavin-containing monooxygenases, called fmo-2, that is induced downstream of DR and hypoxic response and was recently reported to be both necessary and sufficient to increase health and longevity in the nematode C. elegans. Interestingly, previous studies also report induction of FMO homologs in mammalian systems under DR and other longevity- increasing conditions. These results, combined with the knowledge that FMOs are well-conserved across taxa, make understanding the mechanisms of FMO-2-mediated life extension a crucial next step. This project will investigate the endogenous substrates and downstream processes of FMO-2 that are necessary for its longevity benefits. To this end, I will determine the key substrate(s) of FMO-2 protein that are required for its longevity benefits by first identifying potential substrates using untargeted metabolomics approach, validating the substrates using enzymatic assay, and testing the necessity of these substrates using RNAi lifespan analysis (Aim 1). Concurrently, I will determine the downstream metabolic processes that are required for fmo- 2-mediated longevity benefits by generating and improving on my current computational model, and testing the model prediction using isotope tracer flux analysis and RNAi lifespan screen (Aim 2). To ensure their success, these assays will be performed under the guidance of experts in nematode biology and aging, metabolomics profiling and data analysis, in silico modeling, and in vitro biochemistry. Collectively, these aims will further our mechanistic understanding of a highly conserved enzyme family whose member serves as a critical convergence point for multiple longevity pathways. This knowledge will allow us to identify potential therapeutic targets in the form of small molecules, genes, or proteins that can be utilized to improve human health.

项目总结。衰老是多种主要死亡原因的最大风险因素，例如心脏病、多种类型的死亡因此，癌症和阿尔茨海默氏病是全球日益严重的经济和健康问题。 65岁以上的人口数量持续增加，多种遗传和环境途径导致。使用动物模型发现了延缓衰老的机制，例如饮食限制（DR）和缺氧反应。然而，这些途径延长寿命的机制在很大程度上仍不清楚。专注于外源代谢酶家族的成员，含黄素单加氧酶，称为 fmo-2，它是 DR 和缺氧反应诱导的下游，最近有报道称两者兼有对于增加线虫的健康和寿命来说是必要且充分的。线虫。研究还报告了在 DR 和其他长寿条件下哺乳动物系统中 FMO 同系物的诱导 - 这些结果与 FMO 在各个分类单元中得到良好保存的知识相结合，该项目将让了解 FMO-2 介导的寿命延长机制成为关键的下一步。研究 FMO-2 的内源底物和下游过程，这是其发挥作用所必需的为此，我将确定 FMO-2 蛋白所需的关键底物。首先使用非靶向代谢组学方法识别潜在底物，验证使用酶法检测底物，并使用 RNAi 寿命测试这些底物的必要性分析（目标 1），同时，我将确定 fmo- 所需的下游代谢过程。 2 通过生成和改进我当前的计算模型并测试使用同位素示踪剂通量分析和 RNAi 寿命筛选进行模型预测（目标 2）。这些测定将在线虫生物学和衰老、代谢组学专家的指导下进行分析和数据分析、计算机建模和体外生物化学，这些目标将共同推动我们的发展。对高度保守的酶家族的机制理解，其成员是关键这些知识将使我们能够确定潜在的治疗方法。小分子、基因或蛋白质形式的目标可用于改善人类健康。